Phosphatases represent unique and attractive targets for small-molecule inhibition and pharmacological intervention. The protein phosphorylation/dephosphorylation cycle is one of the major regulatory mechanisms employed by eukaryotic cells to control cellular activities including growth and differentiation, cell-to-cell contacts, the cell cycle, and oncogenesis. It is estimated that more than 10% of the active proteins in a typical mammalian cell are phosphorylated. During protein phosphorylation or dephosphorylation, phosphate groups are transferred from adenosine triphosphate (ATP) molecules to a protein by protein kinases and are removed from the protein by protein phosphatases.
Since nearly all forms of human neoplasias have altered cell cycle control, the role of phosphatases in cell cycle control makes these molecules attractive targets for pharmaceutical intervention. The ability of phosphatase inhibitors to interfere with aberrant cell activity has been demonstrated. For example, the naturally occurring serine/threonine phosphatase inhibitor okadaic acid has been shown to induce apoptosis in myeloid leukemia cells (J. Cell. Physiol. 150, 484 (1992)) and in rat hepatocytes, rat pituitary adenoma cell, human mammary carcinoma cells and human neuroblastoma cells (Exp. Cell Res. 195, 237 (1991)).
Magnesium-dependent protein phosphatases appear to participate in a wide variety of functions including regulating cAMP-activated protein-kinase activity, Ca2+-dependent signal transduction, tRNA splicing, and signal transmission related to heat shock responses. It was reported that the complete cDNA sequence encoding PP2C, alpha isoform (or PP2C-alpha) was cloned from mouse brain. PP2C-alpha (GI or NID Number: 532678; Accession Number: D28117) is a 1387 bp sequence that encodes a protein of 382 amino acids with a calculated molecular mass of 42,432 Da (Gene 145(2), 311-312 (1994)).
Given the importance of magnesium-dependent protein phosphatase in biological and disease processes, a clear need exists for further in vivo characterization, which may aid in the identification and discovery of therapeutics and treatments useful in preventing, ameliorating or correcting dysfunctions or diseases.